Project Summary/Abstract Intravenously administered drug delivery systems, including polymer particles, liposomes, niosomes, and micelles, interact with many blood components that subsequently influence their ability to achieve optimal therapy. Even `stealth' particles absorb proteins that then signal specific biologic responses in cells that they contact. Of particular importance are the signaling events that occur in mononuclear phagocyte system (MPS) cells. It is well established that inflammatory events occur in response to some particle injections. Additionally, there are differences in the phagocytosis response to particles that are related to the proteins that are absorbed to the surface. In recent preliminary experiments, we have examined several micelles some of which exhibit a serum protein dependent anti-inflammation response in macrophages, specifically a surprising up regulation of pro-resolving macrophage markers. Despite similar physical micelle properties (size, shape, ?- potential, and chemistry), a second micelle type examined elicited a pro-inflammatory (M1 or classically activated) phenotype. We believe this difference in macrophage response is due to the difference in proteins? amount of protein and identity of proteins?that absorb to the surface of micelles from serum. Based upon this observation, we designed this exploratory/developmental grant application (R21) to focus on the goal of improving the design of nanoparticle drug delivery systems, particularly by understanding the monocyte and macrophage response to nanoparticles and their protein corona. Our central hypothesis is that the protein corona can modulate the activation toward both pro-inflammatory (M1) and pro-resolving (M2) macrophage and monocyte phenotypes. To achieve the overall goals of the project, we have designed two aims that will be examined in parallel. In the first aim we will determine and quantify the proteins absorbed by micelles from human plasma and serum (Gemeinhart and Hong). In the second aim, we will measure the response of monocytes and macrophages to micelles (Gemeinhart and Koh). The information obtained from the aims in vitro and in vivo will be correlated to establish recommendations to inform design of micelles and how these criteria can influence the response of monocytes and macrophages. In future work, we will strive to extend this to other MPS cells and examine the influence of these particles in specific disease models.